Pharmaceutical formulation for acid-labile compounds

This is a continuation-in-part of U.S. patent application Ser. No. 09/335,575, filed Jun. 18, 1999, now U.S. Pat. No. 6,077,541 which is a divisional of U.S. patent application Ser. No. 08/970,489, filed Nov. 14, 1997, now U.S. Pat. No. 6,096,340 and is a continuation-in part of U.S. patent application Ser. No. 09/143,167, filed Aug. 28, 1998, now U.S. Pat. No. 6,174,548.

The present invention relates to a stable tablet formulation of a pharmaceutical compound or composition, and particularly relates to a stable formulation for an acid-labile compound, e.g., a substituted benzamidazole, such as the proton pump inhibitor, omeprazole.

It is well known that certain therapeutic compounds are sensitive to acidic conditions and can degrade after contact with an acid. For example, the well-known compound, omeprazole, degrades and will not function in its intended manner when it contacts the acidic conditions of the stomach. Historically, alkaline materials were added to a core of omeprazole to buffer or neutralize the environment, i.e., the acidic conditions of the stomach, to which the compound was exposed during use. Enteric coatings were later applied over the omeprazole core to prevent the acidic pH conditions of the stomach from contacting the omeprazole. Providing an enteric coating over the omeprazole core can be satisfactory if the product is administered within a short time after its manufacture. However, if the product is stored under ambient conditions, the acidic residue of the enteric coating can degrade the omeprazole active ingredient before it is administered to a patient.

To solve this problem, certain formulations in the prior art have used a separate layer of a coating agent to coat a pellet core comprising omeprazole and an alkaline material. These coated pellets are thereafter further coated with an additional layer of enteric coating. This technique of providing a separate or second additional coating, i.e., a dual layer, as described in U.S. Pat. No. 4,786,505, can be disadvantageous in that it requires two separate coating steps in its manufacture. Thus, the length of the manufacturing process for the product and the resulting costs are increased.

The applicants have surprisingly discovered a novel formulation which (1) avoids the need to use a separate or dual coating layer to physically isolate an acid-labile active ingredient, for example, substituted benzamidazole such as omeprazole, from the enteric coating layer; and (2) provides a means for manipulating or controlling bioavailability of the active ingredient by providing cohesiveness of the powdered ingredients upon tablet disintegration.

In addition, the subject formulation can advantageously provide a tablet dosage form which is bioequivalent to a capsule dosage form of the same or substantially similar strength. The tablet dosage form can further be advantageous in that the manufacturing process can require fewer steps, e.g., eliminate the need for pellet formation and/or coating of those pellets, and there is no need for the additional expense of providing capsule shells.

The present invention concerns a novel dosage form or formulation for an acid-labile compound, e.g., a substituted benzamidazole such as omeprazole. The subject invention involves the use of an enteric coating agent applied to a core of an active ingredient, such as omeprazole, and a particular binder as a suspension in a suitable solvent. The subject invention further concerns a formulation which employs a unique combination of water-soluble and water insoluble binder which can lend certain advantages to the pharmacokinetics of the active ingredient.

In a preferred embodiment, the subject formulation comprises:

(a) a compressed tablet core made from a granulation comprising

(i) a therapeutically effective amount of an active ingredient, e.g., an acid-labile compound such as a substituted benzamidazole,

(ii) an optional surface active agent,

(iii) a filler,

(iv) a pharmaceutically acceptable alkaline agent, and

(v) a binder; and

(b) a single layer of coating on said core, the coating comprising an enteric coating agent.

Accordingly, it is an object of this invention to provide a pharmaceutical dosage formulation of an acid-labile compound, e.g., a substituted benzamidazole such as omeprazole, which is stable upon prolonged storage, is stable when administered to a patient, and is capable of providing the desired therapeutic effect.

It is also an object of this invention to provide a tablet dosage form of an acid-labile compound, e.g., a substituted benzamidazole such as omeprazole, which is bioequivalent to beaded capsule dosage forms which have an additional intermediate layer of an inert coating material.

It is a further object of this invention to provide a pharmaceutical dosage form of an acid-labile compound, e.g., a substituted benzamidazole such as omeprazole, which is bioequivalent to dosage forms comprising a multiparticulate drug delivery system.

Yet another object of this invention is to provide a stable dosage form of an acid-labile compound, e.g., omeprazole, which may be produced without the need for an intermediate coating layer that separates the tablet core from the enteric coating layer.

These and other objects of the invention will become apparent from a review of the appended specification.

The formulation of the subject invention is preferably based on a compressed tablet core formed from a granulation which comprises an acid-labile compound as an active ingredient, e.g., a substituted benzamidazole such as omeprazole, an optional surface-active agent, a filler, an alkaline material, and a binder.

The granulation core can comprise from about 5 to about 70 wt % and, preferably, can comprise about 10 to about 30 wt % of active ingredient. The formulation is advantageously adapted for use with an acid-labile active ingredient, and is preferably used with a substituted benzamidazole. Substituted benzamidazole are commonly known in the art and include, but are not limited to, proton pump inhibitors, e.g., omeprazole, lansoprazole, pantoprazole, perprazole, and the like, as well as pharmaceutically acceptable salts, isomers, or derivatives thereof.

The surface-active agent can be any pharmaceutically acceptable, non-toxic surfactant, e.g., polysorbate 80 (Tween 80), or the like. The surface-active agent may be present at a level of up to about 5 wt % and, preferably, from about 0.20 to about 2.0 wt %, based on the total weight of the granulation.

The alkaline material can be sodium, potassium, calcium, magnesium or aluminum salts of phosphoric acid, carbonic acid, or citric acid, or can be aluminum/magnesium compounds such as Al 2 O 3 . 6MgO.CO 2 . 12H 2 O, (Mg 6 Al 2 (OH 1-6 CO 3 . 4H 2 O), or MgO.Al 2 O 3 . 2SiO 2 .nH 2 O where n is a whole integer of 2 or more. Alternatively, the alkaline material can be lysine or arginine, or can be an antacid such as aluminum hydroxide, calcium hydroxide, magnesium hydroxide, or magnesium oxide. The alkaline agent is preferably provided at about 10 to about 80 wt % based on the total weight of the granulation, and would be understood by those of ordinary skill in the art to depend on the relative strength of the alkaline material. For example, arginine is typically utilized in the formulation from about 10 to about 60 wt %, and is preferably formulated at about 30 to about 55 wt %.

The binder can be any pharmaceutically acceptable, non-toxic binder such as a water-soluble polymer, e.g., polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, or a water-insoluble polymer, e.g., a polymethacrylic acid copolymer such as Eudragit NE30D. Eudragit NE30D is commercially available as a 30% aqueous dispersion. Preferably, the subject formulation comprises the unique combination of both a water-soluble and water-insoluble binder. The binder, whether as a water-soluble, water-insoluble, or as a combination, is preferably provided up to about 10 wt % in an aqueous medium such as water, or as an aqueous dispersion. More preferably, the binder is provided from about 0.25 to 7.5 wt % based on the total weight of the granulation.

A filler can also be used as a granulation substrate. As well understood in the art, sugars such as lactose, dextrose, sucrose, maltose, or microcrystalline cellulose or the like can be used as fillers in the granulation composition. The filler preferably can be provided from about 20 to 50 wt %, and more preferably about 25 to 40 wt % based on the total weight of the granulation.

A tablet disintegrant, e.g., cornstarch, potato starch, croscarmelose sodium, Crospovidone, or sodium starch glycolate, can also be included in the subject formulation in an effective amount. An effective amount of tablet disintegrant can be provided at about 1 to about 15 wt %, preferably from about 3 to about 8 wt %, based on the total weight of the granulation.

The enteric coating agent can be any pharmaceutically acceptable material which resists acid up to a pH of about 5.0 or higher. Preferably, the enteric coating ingredient is selected from cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, Eudragit NE30D, Eudragit L (polymethacrylic acid:methylmethacrylate, 1:1 ratio; MW (No. Av. 135,000—USP Type A)) or Eudragit S (polymethacrylic acid:methylmethacrylate, 1:2 ratio MW (No. Av. 135,000—USP Type B)) and, most preferably, can be a mixture thereof. For example, Eudragit L100-55 is a 100% polymer solids product while the Eudragit L30-55 product is a 30% w/w aqueous dispersion of the polymer.

The enteric coating agent can also include an inert processing aid in an amount from about 10 to about 50 wt %, and preferably from about 20 to about 40 wt %, based on the total weight of the acid resisting component and the inert processing aid. The inert processing aid can include finely divided forms of talc, silicon dioxide, magnesium stearate or the like.

Typical solvents which may be used to apply the acid resisting component-inert processing aid mixture include isopropyl alcohol, acetone, methylene chloride, the like. Generally the acid-resistant component/inert processing aid mixture will be employed from about 5 to about 20 wt % based on the total weight of the solvent and the acid-resistant component/inert processing aid.

The enteric coating can optionally comprise a plasticizer. Suitable plasticizers for use in the enteric coating include acetyl triethyl citrate, dibutyl phthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, propylene glycol, triacetin, polyethylene glycol and diethyl phthalate. The amount of plasticizer can vary, but will typically be present in amounts up to about 40% w/w based upon the weight of acid resisting component of the coating. More preferably, the plasticizer can be provided at about 10-20% w/w based upon the weight of the acid resisting component.

The granulation is preferably formed by combining the alkaline agent, the active ingredient, e.g., omeprazole, the surface active agent, and the binder with an acceptable solvent. An acceptable solvent can be any low viscosity medium such as water, isopropyl alcohol, acetone, ethanol or the like. Use of solvents such as water usually requires, a solvent weight about three times the weight of the dry components of the coating composition.

After the granulation is formed and dried, the granulation can be tableted by standard procedures as accepted in the art. The tablets can then be directly coated with the enteric coating agent, employing standard coating procedures. A color-imparting agent may be added to the enteric coating agent mixture or a rapidly dissolving seal coat containing color may be coated over the enteric coating agent layer provided that the seal coat is compatible with and does not affect the dissolution of the enteric coating layer. The rapidly dissolving seal coat can, for example, comprise Opadry pink which comprises approximately 91 wt % hydroxypropyl methylcellulose (E-6), color, and about 9 wt % polyethylene glycol applied as a 8-15% w/w solution in purified water. In addition, the color may be provided as “Chromateric” which is available from Crompton & Knowles. This product contains water, talc, TiO 2 , triethyl citrate, propylene glycol, synthetic red iron oxide, potassium sorbate, xanthan gum, sodium citrate, and synthetic yellow iron oxide. If desired, conventional sugar based seal coats can be used which contain FDA-certified dyes.